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NEFRECTOMIA CITORREDUTORA
SIM vs NÃO? PARA QUEM? QUANDO? COMO?
Marcelo Freitas, MD, PhD
CEOF Centro Especializado de Oncologia de FlorianópolisOncologista Clínico
CEPON Centro de Oncologia de Santa Catarina
UFSC Universidade Federal de Santa Catarina
▪ De acordo com a resolução do Conselho Federal de Medicina nº 1595/2000 e Resolução da DiretoriaColegiada da ANVISA nº 96/2008, eu declaro as seguintes atividades relacionadas com a indústriafarmacêutica nos últimos 5 anos:
• Investigador em Pesquisa Clínica: Janssen, BMS, AstraZeneca
• Palestrante em Apresentações científicas: Janssen, Pfizer, Novartis, Astellas
• Atividades de Consultoria: Janssen, Pfizer
• Participação em congressos: Janssen, Astellas, Bayer, Pfizer, BMS
Declaração de conflitos de interesses
NEFRECTOMIA CITORREDUTORA? NÃO
Méjean A, et al. ASCO 2018
NEFRECTOMIA CITORREDUTORA? TALVEZ
1 riskfator?
1 metsite?
Lungonly?
Bulky 1º low mets?
DelayedCN?
N Engl J Med. 2018 Aug 2;379(5):481-482.
Turajlic S, et al. Cell 2018 Apr 19;173(3):581-594.e12.
SWOG 8949: NEPHRECTOMY FOLLOWED BY INTERFERON ALFA-2b COMPARED WITH INTERFERON ALFA-2b ALONE FOR METASTATIC RENAL-CELL CANCER
median OS11.1m (IC 9.2-11.1) vs 8.1m (IC 5.4-9.5)
p=0.05Nephrectomy + IFNa-2b
(n = 120)
IFNa-2b(n = 121)
- mRCC, - ECOG PS 0-1,
- suitable candidate for nephrectomy,
(N = 241)
Flanigan RC, NEJM 2001.
CARMENA: Overall Survival
Slide credit: clinicaloptions.com
mOSNephrectomy → sunitinib 13.9mSunitinib alone 18.4m
HR: 0.89 (95% CI: 0.71-1.10)
(non-inferiority ≤ 1.20)
Overall Survival
Méjean A, et al. ASCO 2018. Abstract LBA3. Méjean A, et al. N Engl J Med. 2018
0102030405060708090
100
0 12 24 36 48 60 72 84 96
64.4
42.6
29.1
55.2
35.025.9
POOR RISK
Heng D, Lancet Oncol. 2013
mOS 43,2 months
mOS 22,5 months
mOS 7,8 months
CARMENA Cancer du Rein Metastatique Nephrectomie et Antiangiogéniques
▪ Final analysis of multicenter, randomized, open-label noninferiority phase III trial
Nephrectomy followed 3-6 wks later bySunitinib 50 mg QD* 4 wks on/2 wks off
(n = 226)
Sunitinib 50 mg (n = 224)
biopsy-confirmed clear-cell mRCC, ECOG PS 0-1,
treated brain mets without recurrence 3 wks post treatment permitted,
suitable candidate for nephrectomy(N = 450)
(326 events)
Stratified by center, MSKCC risk group (intermediate vs high risk)
▪ Primary endpoint: OS
▪ 80% power with 1-sided α = 0.05 to show noninferiority with 576 patients enrolled (observed deaths, n = 456)
▪ Trial was closed due to slow recruitment
Méjean A, et al. NEJM 2018. DOI: 10.1056/NEJMoa1803675 ; Motzer R, et al. NEJM 2018. DOI: 10.1056/NEJMe1806331
This slow and incomplete enrollment raises the possibility that many centers saw few patients with stage IV disease or that when surgeons saw patients with intermediate-risk disease who were likely to benefit from combination therapy, they were unwilling for them to undergo randomization and instead treated them outside the trial.
(43% high-risk)
Sunitinib 50 mg
CARMENA: Baseline Characteristics
Characteristic, n (%)Nephrectomy →
Sunitinib (n = 226)
Sunitinib (n = 224)
Median age, yrs (range)
63 (33-84) 62 (30-87)
Male 169 (74.8) 167 (74.6)
MSKCC risk category▪ Intermediate▪ Poor
n = 225125 (55.6)100 (44.4)
n = 224131 (58.5)93 (41.5)
ECOG PS▪ 0▪ 1
130 (57.5)96 (42.5)
122 (54.5)102 (45.5)
Fuhrman grade of RCC▪ 1 or 2▪ 3 or 4
n = 15077 (51.3)73 (48.7)
n = 15682 (52.6)74 (47.4)
Tumor stage▪ T1▪ T2▪ T3 or T4▪ Tx
n = 675 (7.5)
13 (19.4)47 (70.1)
2 (3.0)
n = 497 (14.3)
13 (26.5)25 (51.0)
4 (8.2)
Characteristic, n (%)Nephrectomy →
Sunitinib (n = 226)
Sunitinib (n = 224)
Node stage▪ N0▪ N1▪ N2▪ Nx
n = 6623 (34.8)13 (19.7)7 (10.6)
23 (34.8)
n = 4918 (36.7)6 (12.2)
13 (26.5)12 (24.5)
Median primary tumor size, mm (range)
88 (6-200) 86 (12-190)
Median no. mets (range)
2 (1-5) 2 (1-5)
Median tumor burden, mm (range)
140 (23-399) 144 (39-313)
Location of mets▪ Lung▪ Bone▪ LN▪ Other
n = 217172 (79.3)78 (35.9)76 (35.0)78 (35.9)
n = 221161 (72.9)82 (37.1)86 (38.9)90 (40.7)
Patient disposition
40 [17.7%] did not receive sunitinib 11 [4.9%] did not receive sunitinib
N= 40 in the 2019 update (18%)
33 for complete to near complete
response at metastatic sites
Secondary CN from 7 months
into the trial until 85 months
Méjean A, et al. NEJM 2018, Méjean A, et al. ASCO 2019
CARMENA
Patient population
Presented By Arnaud Mejean at 2018 ASCO Annual Meeting
CARMENA
A
B
C
-
-
-
ITT
PP1
PP2
Arnaud Mejean at 2019 ASCO Annual Meeting
Arnaud Mejean at 2018 ASCO Annual Meeting
Daniel George at 2018 ASCO Annual Meeting
CARMENA
1 NI=1.20
SURTIME Immediate Surgery or Surgery After Sunitinib in Patients With Metastatic Kidney Cancer
Recrutamento foi difícil
• Clear cell sub-type + tumor primário ressecável assintomático + ≤ 3 fatores de risco (Culp)*
• Pacientes que tinham PD não iam pra NCx
50
49
99Alteração do cálculo da amostra de 458 para 98, com a mudança do EP1º para PFS 28wk.
Axel Bex, JAMA Oncology 2018
Risco intermediário MSKCC (86%)
SURTIME Immediate Surgery or Surgery After Sunitinib in Patients With Metastatic Kidney Cancer
PFS 42.0% vs 43%
(p > 0.99).
mOS 32.4m (95% CI 14.5-65.3) vs
15 m (95% CI 9.3- 29.5).
HR 0.57 (p = 0.03)
Delaying cyto-reductive nephrectomy in metastatic RCC is a viable option!
Axel Bex, JAMA Oncology 2018
mTime on Surveillance: 14,9m
mOS: 44,5m
Lancet Oncol. 2016 Sep;17(9):1317-24.
Escudier, ESMO 2019
Axel Bex, ESMO 2019
Conclusões
▪ Não realizar NC desnecessárias
▪ Estratificar os pacientes em categorias de risco
▪ Pacientes de risco desfavorável : Devem receber primeiro terapia sistêmica
▪ Pacientes de risco intermediário:
provavelmente se beneficiam de terapia sistêmica inicial
NC imediata é uma opção válida para pacientes selecionados - Discussão multidisciplinar
NC tardia, provavelmente é o melhor momento para terapia cirúrgica
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